- Quantitative cascade condensations between o-phenylenediamines and 1,2-dicarbonyl compounds without production of wastes
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o-Phenylenediamines 1 underwent a series of cascade condensations with 1,2-dicarbonyl compounds to afford quantitative yields (eight cases) of heterocycles in solid-state syntheses that avoided waste formation. The products were produced in pure form and did not require purifying workup. The components were ball-milled in stoichiometric ratio, or in exceptional cases they were melted together and heated in the absence of solvents (some of them giving quantitative yields). Benzils and 2-hydroxy-1,4-naphthoquinone afforded quinoxaline derivatives 3 and 5, 2-oxoglutaric acid gave a 3-oxodihydroquinoxaline 7, and oxalic acid afforded the dihydroquinoxaline-2,3-dione 9. This last condensed with la in the melt, to afford a mixture of bis(benzimidazolyl) 10 and fluoflavin 11. Alloxane hydrate provided a 100% yield of the 3-oxodihydroquinoxaline-2-carbonylureas 15/16 at room temperature. Parabanic acid required a melt reaction providing a 78% yield of 3-oxodihydroquinoxalinyl-2-urea 22 and side products. Despite numerous reaction steps, most of these uncatalyzed stoichiometric reactions proceeded quantitatively in the solid state to give only one product (plus water), with unsurpassed atom economy. If catalysis with HCl was tried, the results were inferior. If melt reactions were required it appeared to be advantageous to have the products crystallize directly at the reaction temperature. The synthetic results have been interpreted mechanistically and compared to some similar solution reactions that do not exhibit the benefits of the solid-state techniques. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002).
- Kaupp, Gerd,Naimi-Jamal, M. Reza
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- Triazolo[4,3-a] quinoxaline and [1,2,4]triazolo[4,3- a] quinoxaline-1-thiol-derived DNA intercalators: Design, synthesis, molecular docking, in silico ADMET profiles and anti-proliferative evaluations
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In view of their DNA intercalation activities as anticancer agents, 17 novel [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 cells. Molecular docking studies were performed to investigate the binding modes of the proposed compounds with the DNA active site. The data obtained from biological testing highly correlated with those obtained from the molecular modeling studies. MCF-7 was found to be the most sensitive cell line to the influence of the new derivatives. In particular, compound 12d was found to be the most potent derivative of all the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines, with IC50 = 22.08 ± 2.1, 27.13 ± 2.2 and 17.12 ± 1.5 μM, respectively. Although this compound displayed nearly one third of the activity of doxorubicin (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 μM, respectively), it may be useful as a template for future design, optimization, and investigation to produce more potent anticancer analogs. Compounds 12a, 10c and 10d displayed very good anticancer activities against the three HepG2, HCT116 and MCF-7 cancer cell lines, with IC50 = 31.40 ± 2.8, 28.81 ± 2.4 and 19.72 ± 1.5 μM for 12a, 33.41 ± 2.9, 29.96 ± 2.5 and 24.78 ± 1.9 μM for 10c, and 37.55 ± 3.3, 30.22 ± 2.6 and 25.53 ± 2.0 μM for 10d. The most active derivatives, 10c, 10d, 10h, 12a, 12b and 12d, were evaluated for their DNA binding activities. Compound 12d displayed the highest binding affinity. This compound potently intercalates DNA at a decreased IC50 value (35.33 ± 1.8 μM), which is nearly equipotent to that of doxorubicin (31.27 ± 1.8 μM). Compounds 12a and 10c exhibited good DNA-binding affinities, with IC50 values of 39.35 ± 3.9 and 42.35 ± 3.9 μM, respectively. Finally, compounds 10d, 10h and 12b showed moderate DNA-binding affinities, with IC50 values of 50.35 ± 3.9, 57.08 ± 3.3 and 59.35 ± 3.2 μM, respectively.
- El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Sakr, Helmy,Elwan, Alaa
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- NHD2-15, a novel antagonist of Growth Factor Receptor-Bound Protein-2 (GRB2), inhibits leukemic proliferation
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The majority of chronic myeloid leukemia (CML) cases are caused by a chromosomal translocation linking the breakpoint cluster region (BCR) gene to the Abelson murine leukemia viral oncogene-1 (ABL1), creating the mutant fusion protein BCR-ABL1. Downstream of BCR-ABL1 is growth factor receptor-bound protein-2 (GRB2), an intracellular adapter protein that binds to BCR-ABL1 via its src-homology-2 (SH2) domain. This binding constitutively activates growth pathways, downregulates apoptosis, and leads to an over proliferation of immature and dysfunctional myeloid cells. Utilizing novel synthetic methods, we developed four furo-quinoxaline compounds as GRB2 SH2 domain antagonists with the goal of disrupting this leukemogenic signaling. One of the four antagonists, NHD2-15, showed a significant reduction in proliferation of K562 cells, a human BCR-ABL1+ leukemic cell line. To elucidate the mode of action of these compounds, various biophysical, in vitro, and in vivo assays were performed. Surface plasmon resonance (SPR) assays indicated that NHD2-15 antagonized GRB2, binding with a KD value of 119 ± 2 μM. Cellulose nitrate (CN) assays indicated that the compound selectively bound the SH2 domain of GRB2. Western blot assays suggested the antagonist downregulated proteins involved in leukemic transformation. Finally, NHD2-15 was nontoxic to primary cells and adult zebrafish, indicating that it may be an effective clinical treatment for CML.
- Lewis, Tina R.,Smith, Jesse,Griffin, Kallie,Aguiar, Stephanie,Rueb, Kristen F.,Holmberg-Douglas, Natalie,Sampson, Ellen M.,Tomasetti, Skylar,Rodriguez, Sofia,Stachura, David L.,Arpin, Carolynn C.
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- Design, synthesis, molecular docking and anti-proliferative evaluations of [1,2,4]triazolo[4,3-a]quinoxaline derivatives as DNA intercalators and Topoisomerase II inhibitors
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In view of their DNA intercalation activities as anticancer agents, novel twenty four [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 as DNA intercalators and Top II enzyme inhibitors. The data obtained from molecular modeling studies revealed that, our small aromatic molecules were concluded to act through two ways firstly, through non-covalent interaction with the directly bound proteins to DNA hence inhibit topoisomerase-II enzyme. The second is through non-covalently binding to double helical structures of DNA either by intercalating binder as in compounds 10a and 11d or by minor groove binding as in compounds 8e and 8c. Cytotoxic activity indicated that MCF-7 and HepG2 were the most sensitive cell lines to the influence of the new derivatives respectively. In particular, compounds 10a, 11d and 8e were found to be the most potent derivatives overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC50 = (4.55 ± 0.3, 6.18 ± 0.8 and 3.93 ± 0.6 μM), (5.61 ± 0.5, 6.49 ± 0.5and 3.71 ± 0.3 μM) and (4.66 ± 0.3, 8.08 ± 0.8 and 5.11 ± 0.7 μM) respectively. The three derivatives exhibited higher activities than doxorubicin, (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 μM respectively), against HepG2 and MCF-7 but 8e exhibited nearly the same activity against HCT116 cancer cell lines respectively. The most active derivatives 8a-e, 10a,b, 11b-e, 13a and 14b,c were evaluated for their DNA binding activities. The tested compounds displayed very good to moderate DNA-binding affinities. Compounds 10a 11d, 8e, 8c, 8a and 8b displayed the highest binding affinities. These compounds potently intercalate DNA at decreased IC50 values of 25.27 ± 1.2, 27.47 ± 2.1, 27.54 ± 3.2, 27.78 ± 1.3, 29.15 ± 1.8 and 30.23 ± 3.7 μM respectively, which were less than that of doxorubicin (31.27 ± 1.8). Furthermore, the most active cytotoxic compounds 8a, 8b, 8c, 8e, 10a and 11d were selected to evaluate their inhibitory activities against Topo II enzyme. All the tested compounds could interfere with the Topo II activity. They exhibited very good inhibitory activities with IC50 values ranging from 0.379 ± 0.07 to 0.813 ± 0.14 μM that were lower than that of doxorubicin (IC50 = 0.94 ± 0.4 μM). For a great extent, the reported results were in agreement with that of in vitro cytotoxicity activity, DNA binding and molecular modeling studies.
- El-Adl, Khaled,El-Helby, Abdel-Ghany A.,Sakr, Helmy,Elwan, Alaa
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- The use of diethylene glycol in the synthesis of 2,2'-bibenzimidazole from o-phenylenediamine and oxalic acid
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One- and two-step syntheses of 2,2'-bibenzimidazole were compared. Diethylene glycol was used as solvent that provides good solubility of the substrates. The limitation of the one-step preparation is the formation of the by-product, fluoflavine. The two-step synthesis proceeds with the separation of the intermediate product, 1,4-dihydroquinoxaline-2,3-dione, and the final product is only 2,2'-bibenzimidazole. The total yield of the two-step synthesis is above 85%.
- Madrzak-Litwa, Iwona,Borowiak-Resterna, Aleksandra
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- Structural investigation, DNA interactions and in?vitro anticancer studies of transition metal complexes of 3-(2-(2, 4-dihydroxy benzylidene) hydrazinyl) quinoxalin-2(1H) -one
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The Schiff base ligand, 3-(2-(2, 4-dihydroxybenzylidene) hydrazinyl) quinoxalin-2(1H)-one (RHQO) has been synthesized and characterized by spectral and single crystal X-ray analysis. The Mn(II), Ni(II) and Cu(II) complexes of RHQO have been synthesized and characterized by FT-IR, UV-VIS, mass, EPR spectra, CHN, thermo gravimetric analysis, magnetic susceptibility and conductivity measurements. The morphology of the ligand and complexes is studied by Scanning Electron Microscopy. The metal complexes formed were found to be polymeric in nature. The abilities of the ligand and its metal complexes to interact and bind with calf thymus DNA (CT-DNA) has been studied by electronic absorption spectroscopy and their quantitative binding strength was evaluated in terms of their intrinsic binding constant (Kb). The cleavage interaction of the ligand and its metal complexes with super coiled pBR 322 DNA has been investigated by agarose gel electrophoresis. Cytotoxicity of the Cu(II) and Ni(II) complexes was evaluated using various cancer cell lines, Human cervical cancer cell line (Hela), B16 melanoma F10(B16-F10), Human ovarian cancer cell (SKOV3) and Breast cancer cell line (MCF7) by MTT assay. The results indicated that the ligand and its metal complexes bind with CT-DNA by groove binding mode and cleaved the supercoiled pBR 322 DNA in to nicked form. The Ni(II) and Cu(II) complexes exhibited anticancer activity without affecting the normal CHO-K1 cell lines. Communicated by Vsevolod Makeev.
- Sukanya, Panaganti,Reddy, Chittireddy Venkata Ramana
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- Identification of new [1,2,4]triazolo[4,3-a]quinoxalines as potent VEGFR-2 tyrosine kinase inhibitors: Design, synthesis, anticancer evaluation, and in silico studies
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Tumor angiogenesis is mainly regulated by VEGFR-2. In this study, a new series of [1,2,4]triazolo[4,3-a]quinoxaline based-derivatives has been designed and synthesized to develop new anti-proliferative and anti-VEGFR-2 members. Anti-proliferative activities of the synthesized compounds were tested against MCF-7 and HepG2 cell lines. Compound 19a exhibited the highest activity towards both MCF-7 and HepG2 cell lines (IC50 = 8.2 and 5.4 μM, respectively), compared to sorafenib (IC50 = 3.51 and 2.17 μM, respectively). Additionally, all compounds were screened to evaluate their effect as VEGFR-2 inhibitors. Compound 19a (IC50 = 3.4 nM) exhibited good activity compared to sorafenib (IC50 = 3.12 nM). Furthermore, compound 19a disrupted the HepG2 cell cycle by arresting the G2/M phase. Also, marked increase in the percentage apoptotic cells was achieved by compound 19a. The induced apoptotic effect of compound 19a in HepG2 cells was assured by increased pro‐apoptotic marker (Bax) expression by 2.33-fold and decreased anti‐apoptotic (Bcl‐2) expression by 1.88-fold, resulting in an elevation of the Bax/Bcl-2 ratio in HepG2 cells. Comparing to the control cells, compound 19a induced an increase in expression of cleaved caspase-3 and caspase-9 by 2.44- and 2.69-fold, respectively. Finally, the binding modes of the target derivatives were investigated through docking studies against the proposed molecular target (VEGFR-2, PDB ID: 2OH4).
- Alsaif, Nawaf A.,Taghour, Mohammed S.,Alanazi, Mohammed M.,Obaidullah, Ahmad J.,Alanazi, Wael A.,Alasmari, Abdullah,Albassam, Hussam,Dahab, Mohammed A.,Mahdy, Hazem A.
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- Synthesis and characterization of some novel quinoxaline-2, 3-dione derivatives: A preliminary investigation on their activity against a human epithelial carcinoma cell line
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Quinoxaline-2, 3-dione obtained from cyclocondensation reaction of o-phenylene diamine with oxalic acid, was reacted with chlorosulphonic acid under cold condition followed by a reaction with various benzimidazoles to give 2, 3- dioxo-1, 2, 3, 4-tetrahydroquinoxaline-6-sulphonyl benzimidazoles in satisfactory yield. Their structures were confirmed using 1H NMR, IR and mass analysis. Cytotoxicity of these derivatives were evaluated by growth inhibition of HEp-2 cells in vitro. The preliminary bioassay indicated that these compounds showed moderate cytotoxicity.
- Jubie, Selvaraj,Gayathri, Rajamanickam,Srividya, Ammayappan Byung,Kalirajan, Rajagopal,Prabitha, Prabakaran,Sankar, Sundaram,Elango, Kannan
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- Ytterbium triflate catalyzed heterocyclization of 1,2-phenylenediamines and alkyl oxalates under solvent-free conditions via phillips reaction: A facile synthesis of quinoxaline-2,3-diones derivatives
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Ytterbium triflate are found to catalyze efficiently the Phillips-type heterocyclization reactions of 1,2-phenylenediamine and alkyl oxalate under solvent-free and mild conditions to afford the corresponding quinoxaline-2,3-dione derivatives in high yields. The catalyst could be recovered almost quantitatively from the aqueous layer after the reaction was completed and it could be reused in subsequent reaction without decrease in activity.
- Wang, Limin,Liu, Jijun,Tian, He,Qian, Changtao
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- Synthesis, characterization and in vitro anticancer, DNA binding and cleavage studies of Mn (II), Co (II), Ni (II) and Cu (II) complexes of Schiff base ligand 3-(2-(1-(1H-benzimidazol-2-yl)ethylidene)hydrazinyl)quinoxalin-2(1H)-one and crystal structure of the ligand
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A Schiff base ligand, 3-(2-(1-(1H-benzimidazol-2-yl)ethylidene)hydrazinyl)quinoxalin-2(1H)-one (BZHQO), has been synthesized by the condensation of 3-hydrazinylquinoxalin-2(1H)-one and 1-(1H-benzoimidazol-2-yl) ethanone and characterized using spectral and single-crystal X-ray analyses. Mn (II), Co (II), Ni (II) and Cu (II) complexes of the BZHQO ligand have been synthesized and characterized. The interactions of the ligand and its metal complexes with calf thymus DNA have been investigated using absorption spectroscopy and the intrinsic binding constant has been evaluated. Agarose gel electrophoresis has been performed to study the abilities of the ligand and its metal complexes to cleave supercoiled pBR322 DNA into nicked circular form. In vitro anticancer activities of the Cu (II) and Ni (II) complexes have been investigated by MTT assay, using the cell lines HeLa, B16-F10, SKOV3 and MCF7. The Cu (II) complex has been found to be active against HeLa, B16-F10 and MCF7, while the Ni (II) complex has been found to be active against MCF-7.
- Sukanya, Panaganti,Venkata Ramana Reddy, Chittireddy
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- Facile synthesis and anti-proliferative activity evaluation of quinoxaline derivatives
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A series of “drug-like” compounds based on quinoxaline scaffold with arylsulfonyl hydrazinyl, arylformyl hydrazinyl or arylsulfonyl groups at C-2 and aryloxy groups at C-3, were synthesized in 4 or 5 steps involving cyclization, chlorination and coupling reactions. Cellular anti-proliferative activities of these quinoxaline derivatives in vitro were determined, which revealed that the inhibitory potency and selectivity of 6f was comparable to that of the positive control.
- Li, Zhulai,Lin, Jin,Wang, Jian,Wang, Panpan,Xu, Xiuzhi,Xue, Guozhen,Zha, Daijun,Zhang, Zemin
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- Synthesis and Biological Evaluation of Some N-Substituted Quinoxaline Derivatives as Antitumor Agents
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Abstract: A new hybrid molecules containing 1-(N-substituted)-quinoxaline derivatives were synthesized from condensation of 3-hydroxy-2-oxo quinoxaline with 2,3-unsaturated carbonyl compounds under different conditions in order to yield ester and amide derivatives. The structure of the prepared compounds was elucidated on the bases of IR, 1H NMR, 13C NMR, mass and elemental analyses. All the prepared compounds were evaluated for their anticancer activity against two cancer cell line (MCF-7 and Hela). Cell cycle analysis of 3-(p-methoxyphenyl)-3-(3-hydroxy-2-oxoquinoxalin-1-yl)-2-cyanoacrylic acid hydrazides compound demonstrated cell cycle arrest at S phase and Pre-G1 apoptosis. DNA synthesis inhibitory percentage revealed that this mentioned compound showed equipotent activity to Doxorubicin. Additionally, apoptosis was confirmed by increase the percentage of caspase 3/7 higher than Cisplatin.
- Adil, A. Gobouri
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- Synthesis of Novel Substituted Phenyl-3-Hydrazinyl-Quinoxaline-2-Amine Derivatives: Evaluation of Antimicrobial Activity and Its Molecular Docking Studies
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New series of quinoxaline derivatives (4a–4h) were synthesized by treating 2-chloro-3-hydrazinyl quinoxalin (3) with various anilines. Compound 3 was obtained from the 2,3-dichloroquinoxaline 2 which was prepared from 4-dihydroquinoxaline-2,3-dione (1). All synthesized compounds (4a–4h) were characterized by various spectral techniques, that is, IR, 1H-NMR, mass spectroscopy, and elemental analysis and completion of reaction were confirmed by TLC. In vitro antimicrobial activity of synthesized compounds was evaluated using disc diffusion assay against gram-positive and gram-negative microbial strains, and then, the minimum inhibitory concentration and IC50 values of compounds were also determined. The results of antimicrobial study revealed that compounds 4e, 4g, and 4a were active and exhibited better inhibitory activities as compared with standard drug amoxicillin. Docking studies were performed by using Argus lab, and all the compounds exhibited good docking scores between ?9.53 and ?7.94?kcal/mol against dihydrofolate reductase protein fragment from Staphylococcus aureus (PDB ID-4XE6). Among all compounds, 4e has shown the maximum docking score and found in agreement to in vitro studies.
- Paliwal, Sarvesh,Sharma, Swapnil,Dwivedi, Jaya,Mishra, Achal
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- Design, Synthesis, and Characterization of Quinoxaline Derivatives as a Potent Antimicrobial Agent
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A series of quinoxalinone derivatives were synthesized by the reaction of o-phenylenediamine with oxalic acid to yield 1, 4-dihydro quinoxaline-2, 3-dione (1) and then treated with thionyl chloride to yield 2, 3 dichloro quinoxaline (2). This was further reacted with hydrazine hydrate to produce 2, 3-dihydrazinyl quinoxaline (3). This was finally reacted with substituted aromatic aldehydes to produce 2,3-bis[2-(sustituted benzylidine) hydrazinyl] quinoxalines (4). These quinoxalinone derivatives were characterized by infrared spectroscopy and nuclear magnetic resonance spectroscopy and MASS spectral data. All the synthesized compounds were evaluated for their antimicrobial activity. The results of the antimicrobial study revealed that compounds 4c, 4d, and 4i were active and exhibited better inhibitory activities as compared to standard drug ciprofloxacin. The results were further checked with protein legend interaction by using docking studies, and all the compounds exhibited good docking scores between ?8.72 and ?11.29?kcal/mol against dihydrofolate reductase protein fragment from Staphylococcus aureus (PDB ID-4XE6). Among all compound, 4c has shown maximum docking score and found in agreement to in vitro studies.
- Dewangan, Dhansay,Nakhate, Kartik,Mishra, Achal,Thakur, Alok Singh,Rajak, Harish,Dwivedi, Jaya,Sharma, Swapnil,Paliwal, Sarvesh
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- Experimental and ab initio calculational studies on 2,3-diketo- benzopiperazine
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The title compound, 2,3-diketo-benzopiperazine, has been synthesized and characterized by elemental analysis, IR, electronic spectroscopy and single crystal X-ray diffraction. Ab initio calculations of the structure, natural bond orbital, topological analysis and thermodynamic functions of the title compound were performed at HF/6-311G** and B3LYP/6-311G** levels of theory. Vibrational frequencies were also predicted, assigned, compared with the experimental values, and they supported each other. Electronic absorption spectra were calculated by the time-dependent density functional theory, which indicates that the two absorption bands are mainly derived from the contribution of bands π→π*. The calculation of the second order optical non-linearity was carried out, and the molecular hyperpolarisability was 3.282×10-30 esu.
- Jian, Fang-Fang,Zhao, Pu-Su
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- Discovery and evaluation of novel synthetic 5-alkyl-4-oxo-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-1-carbox-amide derivatives as anti-inflammatory agents
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To develop novel anti-inflammatory agents, a series of 5-alkyl-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide derivatives were designed, synthesised, and evaluated for anti-inflammatory effects using RAW264.7 cells. Structures of the synthesised compounds were determined using 1H NMR, 13C NMR, and HRMS. All the compounds were screened for anti-inflammatory activity based on their inhibitory effects against LPS-induced NO release. Among them, 5-(3,4,5-trimethoxybenzyl)-4-oxo-4,5-dihydro-[1, 2, 4]triazolo[4,3-a]quinoxaline-1-carboxamide (6p) showed the highest anti-inflammatory activity and inhibited NO release more potently than the lead compound D1. Further studies revealed that compound 6p reduced the levels of NO, TNF-α, and IL-6, and that its anti-inflammatory activity involves the inhibition of COX-2 and iNOS and downregulation of the mitogen-activated protein kinases (MAPK) signal pathway. Notably, compound 6p displayed more prominent anti-inflammatory activity than D1 and the positive control ibuprofen in the in vivo acute inflammatory model. Overall, these findings indicate that compound 6p is a therapeutic candidate for the treatment of inflammation.
- Shen, Qing-Kun,Gong, Guo-Hua,Li, Gao-,Jin, Mei-,Cao, Li-Hua,Quan, Zhe-Shan
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- Synthesis and positive inotropic activity of [1,2,4]triazolo[4,3-a] quinoxaline derivatives bearing substituted benzylpiperazine and benzoylpiperazine moieties
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In an attempt to search for more potent positive inotropic agents, two series of [1,2,4]triazolo[4,3-a] quinoxaline derivatives bearing substituted benzylpiperazine and benzoylpiperazine moieties were synthesized and their positive inotropic activities evaluated by measuring left atrial stroke volume in isolated rabbit heart preparations. Several compounds showed favorable activities compared with the standard drug, milrinone. Compound 6c was the most potent agent, with an increased stroke volume of 12.53% ± 0.30% (milrinone: 2.46% ± 0.07%) at 3 × 10-5 M. The chronotropic effects of compounds having considerable inotropic effects were also evaluated.
- Liu, Xue-Kun,Ma, Long-Xu,Wei, Zhi-Yu,Cui, Xun,Zhan, Shi,Yin, Xiu-Mei,Piao, Hu-Ri
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- Theoretical and experimental investigation of acidity of the glutamate receptor antagonist 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione and Its Possible Implication in GluA2 Binding
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The acidity of organic compounds is highly relevant to understanding several biological processes. Although the relevance and challenges in estimating pKa values of organic acids is recognized by several reported works in the literature, there is a lack in determining the acidity of amides. This paper presents an experimental/theoretical combined investigation on the acid dissociation of the compound 6,7-dinitro-1,4-dihydroquinoxaline-2,3-dione (DNQX), a well-established antagonist of ionotropic glutamate receptor GluA2. DNQX was synthesized, and its two acidic constants were determined by UV-vis spectroscopy. The experimental pKa of 6.99 ± 0.02 and 10.57 ± 0.01 indicate that DNQX mainly exists as an anionic form (DNQXA1) in physiological media, which was also confirmed by 1H NMR analysis. Five computational methods were applied for estimating the theoretical pKa values of DNQX, including B3LYP, M06-2X, ωB97XD, and CBS-QB3, which were able to provide reasonable estimates for pKa associated with DNQX. Molecular dynamics studies have demonstrated that DNQXA1′ binds more effectively to the pocket of the GluA2 than neutral DNQX, and this fact is coherent to the interactions between amidic oxygens and Arg845 being the main interactions of this host-guest system. Moreover, interaction of GluA2 with endogenous glutamate is stronger than that with DNQXA1, which is in agreement with literature. To the best of our knowledge, we report herein an unprecedented approach involving acidity of the antagonist DNQX, as well as the possible implications in binding to GluA2.
- De Freitas, Gutto R.S.,Coelho, Sara E.,Monteiro, Norberto K.V.,Neri, Jannyely Moreira,Cavalcanti, Lívia Nunes,Domingos, Josiel B.,Vieira, Davi S.,De Souza, Miguel A.F.,Menezes, Fabrício G.
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- Graph Theoretical Analysis, in Silico Modeling, Synthesis, Anti-Microbial and Anti-TB Evaluation of Novel Quinoxaline Derivatives
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Background We designed to synthesize a number of 2-(2-(substituted benzylidene) hydrazinyl)-N-(4-((3-(phenyl imino)-3,4-dihydro quinoxalin-2(1 H)-ylidene)amino) phenyl) acetamide S1-S13 with the hope to obtain more active and less toxic anti-microbial and anti-TB agents. Methods A series of novel quinoxaline Schiff bases S1-S13 were synthesized from o-phenylenediamine and oxalic acid by a multistep synthesis. In present work, we are introducing graph theoretical analysis to identify drug target. In the connection of graph theoretical analysis, we utilised KEGG database and Cytoscape software. All the title compounds were evaluated for their in-vitro anti-microbial activity by using agar well diffusion method at three different concentration levels (50, 100 and 150 μg/ml). The MIC of the compounds was also determined by agar streak dilution method. Results The identified study report through graph theoretical analysis were highlights that the key virulence factor for pathogenic mycobacteria is a eukaryotic-like serine/threonine protein kinase, termed PknG. All compounds were found to display significant activity against entire tested bacteria and fungi. In addition the synthesized scaffolds were screened for their in vitro antituberculosis (anti-TB) activity against Mycobacterium tuberculosis (Mtb) strain H 37 Ra using standard drug Rifampicin. Conclusion A number of analogs found markedly potent anti-microbial and anti-TB activity. The relationship between the functional group variation and the biological activity of the evaluated compounds were well discussed. The observed study report was showing that the compound S6 (4-nitro substitution) exhibited most potent effective anti-microbial and anti-TB activity out of various tested compounds.
- Saravanan, Govindaraj,Selvam, Theivendren Panneer,Alagarsamy, Veerachamy,Kunjiappan, Selvaraj,Joshi, Shrinivas D.,Indhumathy, Murugan,Kumar, Pandurangan Dinesh
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- Design, synthesis, and molecular docking studies of new [1,2,4]triazolo[4,3-a]quinoxaline derivatives as potential A2B receptor antagonists
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Abstract: Many shreds of evidence have recently correlated A2B receptor antagonism with anticancer activity. Hence, the search for an efficient A2B antagonist may help in the development of a new chemotherapeutic agent. In this article, 23 new derivatives of [1,2,4]triazolo[4,3-a]quinoxaline were designed and synthesized and its structures were confirmed by different spectral data and elemental analyses. The results of cytotoxic evaluation of these compounds showed six promising active derivatives with IC50 values ranging from 1.9 to 6.4?μM on MDA-MB 231 cell line. Additionally, molecular docking for all synthesized compounds was performed to predict their binding affinity toward the homology model of A2B receptor as a proposed mode of their cytotoxic activity. Results of molecular docking were strongly correlated with those of the cytotoxic study. Finally, structure activity relationship analyses of the new compounds were explored. Graphic abstract: [Figure not available: see fulltext.]
- Ezzat, Hany G.,Bayoumi, Ashraf H.,Sherbiny, Farag F.,El-Morsy, Ahmed M.,Ghiaty, Adel,Alswah, Mohamed,Abulkhair, Hamada S.
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- New bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, in silico studies, and anticancer evaluation
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A new series of bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives were designed and synthesized to have the main essential pharmacophoric features of VEGFR-2 inhibitors. VEGFR-2 inhibitory activities were assessed for the designed compounds. In addition, cytotoxic activity was evaluated for all derivatives against two human cancer cell lines namely, HepG-2 and MCF-7. The most cytotoxic compound 20 h was subjected to further biological investigations including cell cycle, apoptosis, caspase-3, caspase-9, BAX, and Bcl-2 analyses. Different in silico studies as docking, ADMET and toxicity were carried out. The results exhibited that compounds 20b, 20e, 20h and 20m showed promising VEGFR-2 inhibitory activities with IC50 values of 5.7, 6.7, 3.2, and 3.1 μM, respectively. Moreover, these promising members exhibited the highest antiproliferative activities against the two cell lines with IC50 values ranging from 3.3 to 14.2 μM, comparing to sorafenib (IC50 = 2.17 and 3.43 μM against HepG2 and MCF-7, respectively). Additionally, compound 20h induced cell cycle arrest of HepG2 cells at G2/M phase. Also, such compound increased the progress of apoptosis by 3.5-fold compared to the control. As well, compound 20h showed a significant increase in the level of caspase-3 (2.07-fold), caspase-9 (1.72-fold), and BAX (1.83-fold), and a significant decrease in Bcl-2 level (1.92-fold). The in silico studies revealed that the synthesized compounds have binding pattern like that of sorafenib.
- Alanazi, Mohammed M.,Mahdy, Hazem A.,Alsaif, Nawaf A.,Obaidullah, Ahmad J.,Alkahtani, Hamad M.,Al-Mehizia, Abdulrahman A.,Alsubaie, Sultan M.,Dahab, Mohammed A.,Eissa, Ibrahim H.
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- Water superstructures within organic arrays; hydrogen-bonded water sheets, chains and clusters
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A strategy for encouraging the formation of extended water arrays is presented, in which molecules that contain a 1,4-dihydroquinoxaline-2,3-dione core are used as supramolecular hosts for the accommodation of guest water molecules and arrays. These molecules were selected as they contain a hydrophilic oxalamide-based "terminus" that allows water molecules to hydrogen-bond to the host organic molecules as well as to each other. The host molecules also contain a hydrophobic "end" based upon an aromatic ring, which serves to encourage the formation of discrete water clusters in preference to three-dimensional networks, as the water molecules cannot form strong hydrogen bonds with this part of the molecule. A systematic study of several hydrated structures of four organic molecules based on 1,4-dihydroquinoxaline-2,3-dione (qd) is discussed. The organic molecules, qd, 6-methyl-1,4-dihydroquinoxaline-2,3-dione (mqd), 6,7-dimethyl-1,4- dihydroquinoxaline-2,3-dione (dmqd) and 1,4-dihydrobenzo[g]-quinoxaline-2,3- dione (Phqd), act as supramolecular crystal hosts for the clusters of water, with zero-, one- and two-dimensional arrays of water being observed. The hydrogen bonding in the structures, both within the water clusters and between the clusters and organic molecules, is examined. In particular, the structure of dmqd·6H2O contains a two-dimensional water sheet composed of pentagonal and octagonal units. Phqd·3H2O forms a hydrophilic extended structure encouraging the formation of one-dimensional chains consisting entirely of water. Both qd·2H2O and dmqd·2H2O can be considered to form one-dimensional chains, but only by utilising bridging carbonyl groups of the oxalamide moieties to form the extended array; if only the water is considered, zero-dimensional water tetramers are observed. The remaining hydrated structures, [Na+ dmqd-]dmqd·H2O, dmqd·1/3H2O and mqd·1/2H2O, all contain discrete water molecules but do not form extended water structures.
- Oxtoby, Neil S.,Blake, Alexander J.,Champness, Neil R.,Wilson, Claire
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- The anion binding properties bearing neutral cycle amine recognition sites
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(Chemical Equation Presented) O-phenylene-diamine derivative containing colorimetric dinitroquinoxaline has been synthesized. Its UV-vis spectroscopy and 1H NMR investigation reveal that the receptor shows the strong binding ability for AcO-, F-, and H2PO 4-, moderate binding abilities for OH- and almost no binding abilities for Cl-, Br-, and I -. The interaction of the receptor with studied anions achieving the recognition of anions is proposed to come from the N - H. . .F and potential C - H. . .F hydrogen bonding in its neutral form. The results indicate that it is well suitable for the anion complexation, which is presumably contributed to its ring topology possessing a rigidity conjugation system. Moreover, the molecular orbital level of this receptor and its tautomer were further determined by means of theoretical investigations.
- Shang, Xuefang,Xu, Xiufang
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- A new small molecule inhibitor of soluble guanylate cyclase
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Soluble guanylate cyclase (sGC) is a haem containing enzyme that regulates cardiovascular homeostasis and multiple mechanisms in the central and peripheral nervous system. Commonly used inhibitors of sGC activity act through oxidation of the haem moiety, however they also bind haemoglobin and this limits their bioavailability for in vivo studies. We have discovered a new class of small molecule inhibitors of sGC and have characterised a compound designated D12 (compound 10) which binds to the catalytic domain of the enzyme with a KD of 11 μM in a SPR assay.
- Mota, Filipa,Gane, Paul,Hampden-Smith, Kathryn,Allerston, Charles K.,Garthwaite, John,Selwood, David L.
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- Exploration of quinoxaline derivatives as antimicrobial and anticancer agents
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Novel 2 and 3-substituted quinoxaline derivatives were synthesized through various synthetic pathways, among which cyanoacetamide and cyanoacetohydrazide quinoxaline derivatives 4a-c and 11a-c, respectively, were synthesized. Furthermore, methoxy quinoxaline derivatives 3c and quinoxaline derivatives bearing substituted pyridines 6a,b, 12a,b, and 13a,b were designed to be synthesized. However, we have synthesized acrylohydrazide 5a,b and 7/acrylamide derivatives, Schiff base analogues 14a-f, pyrazole derivatives 15a-e, amide derivatives 16a-f, guanidine derivatives 16 g,h as well as, quinoxalin-2-methylallyl propionate derivative 14g. All the synthesized compounds were confirmed via spectral data and elemental analyses. Moreover, the newly synthesized compounds were evaluated for their antimicrobial activity (Gm +ve, Gm ?ve in comparison to Gentamycin a standard) and fungi (in comparison to Ketoconazole as a standard). Thus, compound 16b showed promising antimicrobial activity against B. subtilis, P. vulgaris, and S. mutants with values ranging from 20 to 27-mm zone of inhibition. While compounds 5a, 14e,f, and 16a,c,d,g,h showed potent antimicrobial activity. Moreover, the National Cancer Institute (NCI) selected 20 compounds that were submitted for anticancer screening against 60 types of cancer cell lines. The most active compounds are 5b and 12a where compound 5b containing 2,4-dichlorophenyl moiety at cyanoacetamide linkage of hydrazine quinoxaline backbone exerted significant growth inhibition activity against Leukemia MOLT-4, Renal cancer UO-31, and Breast cancer MCF-7. In addition, compound 12a having 4,6-diaminopyridinone side chain at position-3 of quinoxaline nucleus exhibited remarkable anticancer activity against renal cancer UO-31.
- Bayoumi, Ashraf H.,Ghiaty, Adel H.,Abd El-Gilil, Shimaa M.,Husseiny, Ebtehal M.,Ebrahim, Maha A.
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- Design, Synthesis and Cytotoxic Evaluation of Novel Chalcone Derivatives Bearing Triazolo[4,3-a]quinoxaline Moieties as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects
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A series of hybrid of triazoloquinoxaline-chalcone derivatives 7a–k were designed, synthesized, fully characterized, and evaluated for their cytotoxic activity against three target cell lines: human breast adenocarcinoma (MCF-7), human colon carcinoma (HCT-116), and human hepatocellular carcinoma (HEPG-2). The preliminary results showed that some of these chalcones like 7b–c, and 7e–g exhibited significant antiproliferative effects against most of the cell lines, with selective or non-selective behavior, indicated by IC50 values in the 1.65 to 34.28 μM range. In order to investigate the mechanistic aspects of these active compounds, EGFR TK and tubulin inhibitory activities were measured as further biological assays. The EGFR TK assay results revealed that the derivatives 7a–c, 7e, and 7g could inhibit the EGFR TK in the submicromolar range (0.093 to 0.661 μM). Moreover, an antitubulin polymerization effect was noted for the active derivatives compared to the reference drug colchicine, with compounds 7e and 7g displaying 14.7 and 8.4 micromolar activity, respectively. Furthermore, a molecular docking study was carried out to explain the observed effects and the binding modes of these chalcones with the EGFR TK and tubulin targets.
- Alswah, Mohamed,Bayoumi, Ashraf H.,Elgamal, Kamal,Elmorsy, Ahmed,Ihmaid, Saleh,Ahmed, Hany E. A.
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- Synthesis of 2,3-dichloroquinoxalines via vilsmeier reagent chlorination
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A convenient and high-yielding synthesis of 2,3-dichloroquinoxalines from the corresponding 2,3- dihydroxyquinoxalines has been developed. Treatment of a slurry of the 2,3-dihydroxyquinoxaline 1a-j with N,N-dimethylformamide in the presence of excess thionylchloride in 1,2-dichloroethane results in the rapid and high-yielding formation of the 2,3-dichloroquinoxaline derivatives 2a-j. Simplified workup and purification procedures for these compounds are also described.
- Romer, Duane R.
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- Evaluation of quinoxaline compounds as ligands of a site adjacent to S2 (AS2) of cruzain
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The binding of ten quinoxaline compounds (1–10) to a site adjacent to S2 (AS2) of cruzain (CRZ) was evaluated by a protocol that include a first analysis through docking experiments followed by a second analysis using the Molecular Mechanics-Poisson-Boltzmann Surface Area method (MM-PBSA). Through them we demonstrated that quinoxaline compounds bearing substituents of different sizes at positions 3 or 4 of the heterocyclic ring might interact with the AS2, particularly interesting site for drug design. These compounds showed docking scores (ΔGdock) which were similar to those estimated for inhibitors that bind to the enzyme through non-covalent interactions. Nevertheless, the free binding energies (ΔG) values estimated by MM-PBSA indicated that the derivatives 8–10, which bear bulky substituents at position 3 of the heterocycle ring, became detached from the binding site under a dynamic study. Surprisingly, the evaluation of the inhibitory activity of cruzipain (CZ) of some derivatives showed that they increase the enzymatic activity. These results lead us to conclude about the relevance of AS2 as a pocket for compounds binding site, but not necessarily for the design of anti-chagasic compounds.
- Fabian,Martini, M. Florencia,Sarduy, Emir Salas,Estrin, Darío A.,Moglioni, Albertina G.
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- Synthesis of substituted dipyrido[3,2-a:2′,3′-c]phenazines and a new heterocyclic dipyrido[3,2-f:2′,3′-h]quinoxalino[2,3-b]quinoxaline
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Three new α,α′-diimine ligands were synthesized based on condensation of 1,10-phenanthroline-5,6-dione with 1,2-phenylenediamine derivatives using different approaches. All compounds were fully characterized by IR, 1H and 13C NMR, UV-visible, and MS spectroscopies. We report the first example of a dipyrido[3,2-f:2′,3′-h]quinoxalino[2,3-b]quinoxaline, which exhibits a strong absorption at 430 nm and an interesting electrochemical behavior. These new molecules may have biological potential and are of synthetic and technological importance.
- da Silva Miranda, Fabio,Signori, Aline Maria,Vicente, Juliano,de Souza, Bernardo,Priebe, Jacks?Patrick,Szpoganicz, Bruno,Gon?alves, Norberto Sanches,Neves, Ademir
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- First coordination polymer of 1,4-dihydro-2,3-quinoxalinedione in ketoamine tautomeric form
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The first coordination compound of 1,4-dihydro-2,3-quinoxalinedione in ketoamine tautomeric form (denoted as H2qdione) was reported. H 2qdione was obtained by a solid-state reaction of o-phenylenediamine and oxalic acid. Reaction of this ligand with CdCl2 solvothermally yielded a coordination polymer [Cd(H2qdione)Cl2] n, which was structurally characterized by X-ray diffraction and IR spectroscopy. Continuous Cd2Cl2 diamonds form a double-sided comb with terminal H2qdione-κ2O,O' as the comb teeth. Interaction of these combs through very extensive π-π stacking, C-HA...Cl, and N-HA...Cl hydrogen bonds leads to a novel 3D architecture and significant enhancement of solid-state luminescence of about 10 times compared to the free H2qdione ligand.
- Shi, Ling,Cai, Bin,Huang, Guang,Wu, Jian-Zhong,Yu, Ying
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- Non-symmetrical three and two-core ring mesogens based on quinoxaline and benzimidazole derivatives: Supramolecular layers through amphoteric donating/accepting H-bonds
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Self-assembly-based molecular structures have proven to be highly relevant to the development of soft materials. This work reports the synthesis, thermal behavior and computational analysis of two novel heterocyclic compounds with a non-symmetrical shape bearing a single long alkyl (C12) chain. The compounds 2-(4-dodecyloxy-phenyl)-1H-benzoimidazole, 1, with three-ring core mesogen with a more linear shape, and 1-dodecyl-1,4-dihydro-quinoxaline-2,3-dione, 2, with a condensed two-ring core with a more compact discotic shape, were obtained in good yields and investigated by polarized optical microscopy (POM) and differential scanning calorimetry (DSC) analysis. Benzimidazole derivative 1 was found to present liquid crystalline property, with a mesophase range from 85 to 177 °C, as verified by POM and DSC, with a smectogenic polymorphism assigned as a SmB and a more organized unidentified SmX phase. On the other hand, although quinoxaline 2 did not show liquid crystal behavior, POM analysis indicated an interesting spherulitic packing pattern, typical of a columnar arrangement of the molecules by possible H-bond interactions. Computational results indicated that combining intermolecular hydrogen bonds and hydrophobic interactions lead to a non-planar lamellar model for benzimidazole 1, consistent with the smectic packing found in the liquid crystalline phase and a twist-type packing for compound 2, which is consistent with a spherulitic model.
- de Oliveira, André H.,Silva, Welisson P.,da Silva, Jordan K.,Freitas, Júlio.C.O.,de Souza, Miguel A.F.,Cristiano, Rodrigo,Menezes, Fabrício G.
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- New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis
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New series of [1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one and [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized, and biologically assessed for their anti-proliferative activities against two selected tumor cell lines MCF-7 and HepG2. Comparing to sorafenib (IC50 = 2.17 ± 0.13 and 3.51 ± 0.21 μM against MCF-7 and HepG2, respectively), compound 25d, 25e, 25i, and 27e exhibited the highest activities against the examined cell lines with IC50 values extending from 4.1 ± 0.4 to 11.7 ± 1.1 μM. Furthermore, VEGFR-2 inhibitory activities were assessed for all the synthesized compounds as potential mechanisms for their anti-proliferative activities. Compounds 25d, 25e, 25i, and 27e displayed prominent inhibitory efficiency versus VEGFR-2 kinase with IC50 value ranging from 3.4 ± 0.3 to 6.8 ± 0.5 nM. Fascinatingly, the results of VEGFR-2 inhibitory assays were matched with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited promising VEGFR-2 inhibitory activities. Further studies displayed the ability of compound 25d to induce apoptosis in HepG2 cells and can arrest the growth of such cells at the G2/M phase. Also, compound 25d produced a significant increase in the level of BAX/Bcl-2 ratio (3.8-fold), caspase- 3 (1.8-fold), and caspase-9 (1.9-fold) compared to the control cells. Molecular docking studies were carried out to investigate the possible binding interaction inside the active site of the VEGFR-2.
- Alsaif, Nawaf A.,Dahab, Mohammed A.,Alanazi, Mohammed M.,Obaidullah, Ahmad J.,Al-Mehizia, Abdulrahman A.,Alanazi, Manal M.,Aldawas, Saleh,Mahdy, Hazem A.,Elkady, Hazem
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- Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors
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In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G-2, Hep-2, and Caco-2). Compounds 18b, 19b, 23, 25b, and 26 showed strong potencies against all tested cell lines with IC50 values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 μM, comparable with those of doxorubicin (IC50 values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 μM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC50 = 0.97 ± 0.1 and 1.10 ± 0.1 μM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 μM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC50 value of 37.06 ± 1.8 μM. Moreover, apoptosis and cell-cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G-2 cells. It has revealed cell-cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl-2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA–Topo II complex to examine the binding patterns of the synthesized compounds.
- Eissa, Ibrahim H.,Metwaly, Ahmed M.,Belal, Amany,Mehany, Ahmed B.M.,Ayyad, Rezk R.,El-Adl, Khaled,Mahdy, Hazem A.,Taghour, Mohammed S.,El-Gamal, Kamal M.A.,El-Sawah, Mohamad E.,Elmetwally, Souad A.,Elhendawy, Mostafa. A.,Radwan, Mohamed M.,ElSohly, Mahmoud A.
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- Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors
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Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15a, 15b, and 15d showed IC50 from 17.39 to 47.10 μM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15d which came second with regard to antitumor assay with IC50 = 24.10, 40.90, and 33.40 μM against aforementioned cell lines, respectively. Furthermore, Compound 15d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15d showed IC50 of 253 and 381 nM against HER2 and FGFR, respectively.
- Abdallah, Abdallah E.,Abo-Saif, Mariam A.,Al Ward, Maged Mohammed Saleh,Alesawy, Mohamed S.,Eissa, Sally I.,El-Feky, Ola A.,El-Zahabi, Mohamed Ayman,Elkaeed, Eslam B.,Mabrouk, Reda R.,Mehany, Ahmed B. M.
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p. 573 - 591
(2022/01/20)
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- Synthesis of novel halogenated heterocycles based on o‐phenylenediamine and their interactions with the catalytic subunit of protein kinase ck2
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Protein kinase CK2 is a highly pleiotropic protein kinase capable of phosphorylating hundreds of protein substrates. It is involved in numerous cellular functions, including cell viability, apoptosis, cell proliferation and survival, angiogenesis, or ER‐stress response. As CK2 activity is found perturbed in many pathological states, including cancers, it becomes an attractive target for the pharma. A large number of low‐mass ATP‐competitive inhibitors have already been developed, the majority of them halogenated. We tested the binding of six series of halogenated heterocyclic ligands derived from the commercially available 4,5‐dihalo‐benzene‐1,2‐diamines. These ligand series were selected to enable the separation of the scaffold effect from the hydrophobic interactions attributed directly to the presence of halogen atoms. In silico molecular docking was initially applied to test the capability of each ligand for binding at the ATP‐binding site of CK2. HPLC‐derived ligand hydrophobicity data are compared with the binding affinity assessed by low‐volume differential scanning fluorimetry (nanoDSF). We identified three promising ligand scaffolds, two of which have not yet been described as CK2 inhibitors but may lead to potent CK2 kinase inhibitors. The inhibitory activity against CK2α and toxicity against four reference cell lines have been determined for eight compounds identified as the most promising in nanoDSF assay.
- Maciejewska, Agnieszka Monika,Paprocki, Daniel,Poznański, Jaros?aw,Speina, El?bieta,Winiewska‐szajewska, Maria
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supporting information
(2021/06/09)
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- One-pot, two-step synthesis of substituted triazoloquinoxalinone starting from 3-hydrazineylquinoxalin-2(1H)-one
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An efficient one-pot two-step synthesis of substituted-triazolo[4,3-a]quinoxalin-4(5H)-one has been developed. The 3-hydrazineylquinoxalin-2(1H)-one reacts with respective aldehyde to afford the individual hydrazineylidene intermediate which undergoes oxidative cyclization in the presence of ferric chloride hexahydrate (FeCl3.6H2O) to affords various substituted- triazolo[4,3-a]quinoxalin-4(5H)-one in good to excellent yields.
- Patil, Vikas S,Yadavalli, Subba Rao,Merugu, Ramchander,Swamy,Devunuri, Nagaraju
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supporting information
p. 1994 - 2000
(2021/05/26)
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- Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation
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S. aureus resistant to methicillin (MRSA) is one of the most-concerned multidrug resistant bacteria, due to its role in life-threatening infections. There is an urgent need to develop new antibiotics against MRSA. In this study, we firstly compiled a data set of 2,3-diaminoquinoxalines by chemical synthesis and antibacterial screening against S. aureus, and then performed cheminformatics modeling and virtual screening. The compound with the Specs ID of AG-205/33156020 was discovered as a new antibacterial agent, and was further identified as a Gyrase B (GyrB) inhibitor. In light of the common features, we hypothesized that the 6c as the representative of 2,3-diaminoquinoxalines also inhibited GyrB and eventually proved it. Via molecular docking and molecular dynamics simulations, we identified binding modes of AG-205/33156020 and 6c to the ATPase domain of GyrB. Importantly, these GyrB inhibitors inhibited the MRSA strains and showed selectivity to HepG2 and HUVEC. Taken together, this research work provides an effective ligand-based computational workflow for scaffold hopping in anti-MRSA drug discovery, and discovers two new GyrB inhibitors that are worthy of further development.
- Lian, Xu,Xia, Zhonghua,Li, Xueyao,Karpov, Pavel,Jin, Hongwei,Tetko, Igor V.,Xia, Jie,Wu, Song
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- Design, synthesis and molecular docking of new [1,2,4] triazolo[4,3-a]quinoxaline derivatives as anticancer agents targeting VEGFR-2 kinase
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Abstract: Vascular endothelial growth factor receptor-2 (VEGFR-2) is critically involved in cancer angiogenesis. Blocking of VEGFR-2 signaling pathway proved effective suppression of tumor growth. Accordingly, two series of new triazoloquinoxaline-based derivatives were designed and synthesized as VEGFR-2 inhibitors. All in vitro cytotoxic activities of the synthesized compounds were evaluated against two human cancer cell lines (MCF-7 and HepG2). To confirm the potential mechanism of cytotoxicity, enzymatic assays against VEGFR-2 were estimated for all the target compounds. The results of VEGFR-2 inhibitory activity and cytotoxicity were in high correlation. Compound 22a exhibited the highest cytotoxic effect with IC50 values of 6.2 and 4.9?μM against MCF-7 and HepG2, respectively, comparing to sorafenib (IC50 = 3.53 and 2.18?μM). Such derivative showed the best VEGFR-2 inhibitory activity with an IC50 value of 3.9?nM, which is very close to that of sorafenib (IC50 = 3.13?nM). Moreover, compounds 22b, 23b, and 23e exhibited strong cytotoxic activity with IC50 values ranging from 11.7 to 15.3?μM. Also, these compounds showed promising VEGFR-2 inhibition with IC50 values of 4.2, 5.7, and 4.7?nM, respectively. In silico docking, ADMET, and toxicity studies were carried out for the synthesized compounds. The results revealed that some compounds have a good binding mode against VEGFR-2 and a high level of drug-likeness. Graphic abstract: [Figure not available: see fulltext.]
- Alanazi, Mohammed M.,Alanazi, Wael A.,Alasmari, Abdullah F.,Albassam, Hussam,Alsaif, Nawaf A.,Elwan, Alaa,Mahdy, Hazem A.,Obaidullah, Ahmad J.,Taghour, Mohammed S.
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- New quinoxaline compounds as DPP-4 inhibitors and hypoglycemics: Design, synthesis, computational and bio-distribution studies
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The current work represents the design and synthetic approaches of a new set of compounds 6-10 bearing the 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide scaffold. The biological evaluation revealed that most of the new compounds were promising selective dipeptidyl peptidase-IV (DPP-4) inhibitors and in vivo hypoglycemic agents utilizing linagliptin as a standard drug. The acute toxicity examination confirmed the safety profile of all compounds. Molecular docking studies related the significant DPP-4 suppression activity of compounds 9a, 10a, 10f, 10g to their nice fitting in the active pocket of DPP-4. In addition, the molecular dynamic study exhibited the stability of both 10a and 10g within the active site of DPP-4. The QSAR study showed that the difference between the predicted activities is very close to the experimental suppression effect. Moreover, both compounds 10a and 10g obeyed Lipinski's rule, indicating their efficient oral bioavailability. Compound 10a was radiolabeled, forming the 131I-SQ compound 10a to study the pharmacokinetic profile of this set of compounds. The biodistribution pattern hit the target protein since the tracer accumulated mainly in the visceral organs where DPP-4 is secreted in a high-level, thus with consequent stimulation of insulin secretion, leading to the target hypoglycemic effect.
- Abd El-Karim, Somaia S.,Anwar, Manal M.,Elseginy, Samia A.,Essa, Basma M.,Sakr, Tamer M.,Syam, Yasmin M.
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p. 36989 - 37010
(2021/12/02)
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- Targeting VEGFR-2 by new quinoxaline derivatives: Design, synthesis, antiproliferative assay, apoptosis induction, and in silico studies
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Twelve new triazolo[4,3-a]quinoxaline-based compounds are reported as anticancer agents with potential effects against vascular endothelial growth factor receptor-2 (VEGFR-2), using sorafenib as a reference molecule. With sorafenib as the positive control, the antiproliferative effects of the synthesized compounds against MCF-7 and HepG2 cells, as well as their VEGFR-2-inhibitory activities, were assessed. The most powerful VEGFR-2 inhibitor was compound 14a, which had an IC50 value of 3.2 nM, which is very close to that of sorafenib (IC50 = 3.12 nM). Furthermore, compounds 14c and 15d showed potential inhibitory activity against VEGFR-2, with IC50 values of 4.8 and 5.4 nM, respectively. Compound 14a caused apoptosis in HepG2 cells and stopped the cell cycle at the G2/M phase. In HepG2 cells, it also increased the levels of the proteases caspase-3 and caspase-9, as well as the Bax/Bcl-2 ratio. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and toxicity experiments revealed that the synthesized agents had acceptable drug-likeness.
- Al-Hossaini, Abdullah M.,Al-Mehizi, Abdulrahman A.,Alanazi, Mohammed M.,Alkahtani, Hamad M.,Alsaif, Nawaf A.,Elwan, Alaa,Mahdy, Hazem A.,Obaidullah, Ahmad J.,Taghour, Mohammed S.
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- A new method for the three-step synthesis of the drug molecule 3-(2-thiophene-2-methylene)hydrazinoquinoxaline-2-one
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The present invention discloses a new method for the three-step synthesis of the pharmaceutical molecule 3- (2- thiophene-2-methylene) hydrazinoquinoxaline-2-one. This method takes quinoxaline-2-ketone as the reaction raw material, and constructs the drug molecule 3-(2-thiophene-2-methylene)hydrazinoxaline-2-one by oxidation reaction, hydrazine lysis reaction and condensation reaction. The method of the present invention is simple in means of synthesis, the reaction conditions are mild, and meet the requirements of the development of green chemistry.
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Paragraph 0010; 0025-0026
(2022/01/04)
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- Novel molecular targeting anti-tumor aza-steroid derivative based on lipid toxicity and preparation and application thereof
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The invention provides a novel molecular targeting anti-tumor aza-steroid derivative based on lipid toxicity and a preparation method and application thereof, and belongs to the field of chemical medicines. The derivative is a compound as shown in a formula I, or a salt thereof, or a stereoisomer thereof. The compound is low in toxicity or basically non-toxic to normal cells, has an obvious inhibition effect to tumor cell lines, particularly has good lipid toxicity selectivity to tumor cells such as liver cancer, lung cancer and the like in vivo, and has an obvious inhibition effect; meanwhile, the compound can effectively activate SREBP1 and PPAR gamma, inhibit lipid transport MTTP, cause lipid aggregation in tumor cells and cause lipid toxicity of the tumor cells. The compound can be used for treating liver cancer, lung cancer and the like in a molecular targeting manner, is low in toxicity or even non-toxic, and has a good application prospect.
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Paragraph 0178; 0180; 0181; 0192; 0221
(2021/08/19)
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- Imidazopyrazine organic compound and application thereof
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The invention relates to an imidazopyrazine organic compound and application thereof. The organic compound has a structure as shown in a general formula (1). The organic compound according to the present invention has excellent hole transport properties and stability, can be used as a hole injection layer material in an organic electroluminescent element, and can also be doped in a hole injectionlayer or a hole transport layer as a doping agent, so that a device can be driven at a low voltage, the electroluminescent efficiency can be improved, and the service life of the device can be prolonged.
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Paragraph 0238-0241
(2021/03/30)
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- Design, synthesis and biological evaluation of quinoxaline compounds as anti-HIV agents targeting reverse transcriptase enzyme
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Infection by human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents, more active, less toxic and with increased tolerability to mutations. Quinoxaline derivatives are an emergent class of heterocyclic compounds with a wide spectrum of biological activities and therapeutic applications. These types of compounds have also shown high potency in the inhibition of HIV reverse transcriptase and HIV replication in cell culture. For these reasons we propose, in this work, the design, synthesis and biological evaluation of quinoxaline derivatives targeting HIV reverse transcriptase enzyme. For this, we first carried out a structure-based development of target-specific compound virtual chemical library of quinoxaline derivatives. The rational construction of the virtual chemical library was based on previously assigned pharmacophore features. This library was processed by a virtual screening protocol employing molecular docking and 3D-QSAR. Twenty-five quinoxaline compounds were selected for synthesis in the basis of their docking and 3D-QSAR scores and chemical synthetic simplicity. They were evaluated as inhibitors of the recombinant wild-type reverse transcriptase enzyme. Finally, the anti-HIV activity and cytotoxicity of the synthesized quinoxaline compounds with highest reverse transcriptase inhibitory capabilities was evaluated. This simple screening strategy led to the discovery of two selective and potent quinoxaline reverse transcriptase inhibitors with high selectivity index.
- Estrin, Darío,Fabian, Lucas,Gómez, Natalia,Moglioni, Albertina,Salvatori, Melina,Taverna Porro, Marisa,Turk, Gabriela
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- Synthesis and Antimicrobial Activity of Quinoxaline Based 1,2,3-Triazoles
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Abstract: Synthesis and characterization of novel quinoxaline-1,2,3-triazole hybridheterocyclic derivatives have been carried out, and their antimicrobial activityhas been tested. Antibacterial and antifungal studies of the synthesizedcompounds have demonstrated high to moderate activity against the testedpathogens for most of those. Several products have been determined to be potentantimicrobial agents at concentrations of 75 and 100 μg/mL as compared to thestandard drug Gentamicin.
- Kumar, A. Kishore,Sunitha,Ramesh,Jalapathi
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p. 2386 - 2393
(2021/02/12)
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- Design and synthesis of quinoxaline-1,3,4-oxadiazole hybrid derivatives as potent inhibitors of the anti-apoptotic Bcl-2 protein
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Quinoxaline is one of the privileged heterocyclic fragments for drug molecules. Quinoxaline anticancer drug candidates XK469 and CQS exhibit antiproliferative and proapoptotic properties against various cancers. Based on their chemical structures, we therefore synthesized a series of quinoxaline-1,3,4-oxadiazole hybrids and assessed their anticancer potential on human leukemia HL-60 cells. Although these hybrids exerted significant inhibition of HL-60 cell proliferation, they showed high cytotoxicity on human normal cells (WI-38). Utilizing information from molecular modelling of the hybrids to the anti-apoptotic Bcl-2 protein, we added substructures including phenyl, piperazine, piperidine, and morpholine rings to their frameworks. The designed quinoxaline-1,3,4-oxadiazole hybrid derivatives successfully induced apoptotic response on HL-60 cells with low toxicity on WI-38 cells. Furthermore, RT-PCR analysis demonstrated that these derivatives predominantly inhibit Bcl-2 expression. Our findings highlight the great potential for the development of synthetic quinoxaline-1,3,4-oxadiazole hybrid derivatives as proapoptotic anticancer agents.
- Ono, Yukari,Ninomiya, Masayuki,Kaneko, Daiki,Sonawane, Amol D.,Udagawa, Taro,Tanaka, Kaori,Nishina, Atsuyoshi,Koketsu, Mamoru
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- Beckmann rearrangement: Thiamine hydrochloride as a remarkable catalyst for one-pot synthesis of amides from ketones
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Thiamine hydrochloride catalyzed synthesis of amides from ketones including 3-acetyl coumarin via Beckmann rearrangement has been reported. The reaction is believed to involve oxime formation, cleavage of C[sbnd]C bond followed by C[sbnd]N bond formation in one-pot. Thiamine hydrochloride is stable, cheap, easy to handle and environmentally friendly.
- Mahajan, Sheena,Slathia, Nancy,Kapoor, Kamal K.
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supporting information
(2020/04/08)
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- Design and synthesis of new quinoxaline derivatives as anticancer agents and apoptotic inducers
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The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.
- El Newahie, Aliya M.S.,Nissan, Yassin M.,Ismail, Nasser S.M.,Abou El Ella, Dalal A.,Khojah, Sohair M.,Abouzid, Khaled A.M.
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- Structure, preparation method and application of a series of quinoxalinone derivatives
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The invention provides the structure and synthesis method of a compound shown in the formula I, and application of pharmaceutically acceptable salts of the compound or a mixture of the salts in preparation of drugs for preventing and/or treating diabetic complications. The compound acts as aldose reductase inhibitors and antioxidants and can effectively scavenge free radicals and inhibit the production of lipid peroxides by inhibiting the activity of aldose reductase, and thus the effect of preventing and/or treating the diabetic complications is achieved. The invention further provides a pharmaceutical composition containing the compound and having preventive and/or therapeutic effects on diabetic complications. The formula can be seen in the description.
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Paragraph 0051-0053
(2019/06/27)
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- Structure, preparation method and application of quinoxalinone derivative
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The invention provides a structure and preparation of a quinoxalinone derivative (a compound as shown in formula I) and application of the pharmaceutically acceptable salt of the quinoxalinone derivative in the preparation of drugs for preventing and/or treating diabetic complication. The quinoxalinone derivative serving as a aldose reductase inhibitor and antioxidant can prevent and/or treat thediabetic complication by inhibiting the activity of aldose reductase and effectively scavenging free radicals and lipid peroxide and inhibiting active oxygen at the same time.
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Paragraph 0047; 0049
(2019/06/27)
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- Synthesis and antimicrobial activity of some new substituted quinoxalines
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A number of new symmetrically and asymmetrically 2,3-disubstituted quinoxalines were synthesized through functionalization of 2,3-dichloroquinoxaline (2,3-DCQ) with a variety of sulfur and/or nitrogen nucleophiles. The structures of the obtained compounds were established based on their spectral data and elemental analysis. The antimicrobial activity for the prepared compounds was investigated against four bacterial species and two fungal strains. The symmetrically disubstituted quinoxalines 2, 3, 4, and 5 displayed the most significant antibacterial activity, while compounds 6a, 6b, and the pentacyclic compound 10 showed considerable antifungal activity. Furthermore, compounds 3f, 6b showed broad antimicrobial spectrum against most of the tested strains.
- El-Atawy, Mohamed A.,Hamed, Ezzat A.,Alhadi, Mahjoba,Omar, Alaa Z.
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- Design, synthesis and photoinduced DNA cleavage studies of [1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones
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An expedient and eco-friendly synthesis of 1-aryl/heteroaryl-[1,2,4]-triazolo[4,3-a]quinoxalin-4(5H)-ones (4) has been accomplished via iodobenzene diacetate mediated oxidative intramolecular cyclization of 3-(2-(aryl/heteroarylidene)hydrazinyl)-quinoxalin-2(1H)-ones (3). Ten synthesized compounds 3 and 4 (10–40 μg) on irradiation with UV light at λmax 312 nm could lead to cleavage of supercoiled pMaxGFP DNA (Form I) into the relaxed DNA (Form II) without any additive. Further, DNA cleaving ability of triazoles was quantitatively evaluated and was found to be dependent on its structure, concentration, and strictly on photoirradiation time. Mechanistic investigations using several additives as potential inhibitors/activator revealed that the DNA photocleavage reaction involves Type-I pathway leading to formation of superoxide anion radicals (O2 ? [rad]) as the major reactive oxygen species responsible for photocleavage process.
- Sumran, Garima,Aggarwal, Ranjana,Mittal, Ashwani,Aggarwal, Aviral,Gupta, Amit
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- A One-pot Facile Synthesis of 2,3-Dihydroxyquinoxaline and 2,3-Dichloroquinoxaline Derivatives Using Silica Gel as an Efficient Catalyst
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An efficient one-pot reaction has been developed for the synthesis of 2,3-dichloroquinoxaline derivatives 3a–n. The reaction was performed in two steps via a silica gel catalyzed tandem process from o-phenylenediamine and oxalic acid, followed by addition of phosphorus oxychloride (POCl3). A variety of 2,3-dichloroquinoxalines have been obtained in good to excellent overall yields. Eight known compounds 3a–3h were characterized by IR, 1H-NMR, and mass spectroscopies. Compounds 3i–3n without spectroscopic data were characterized by IR, 1H-NMR, 13C-NMR, and mass spectroscopies.
- Zhang, Pei-Ming,Li, Yao-Wei,Zhou, Jing,Gan, Lin-Ling,Chen, Yong-Jie,Gan, Zong-Jie,Yu, Yu
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p. 1809 - 1814
(2018/07/25)
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- Design, synthesis, molecular modeling and anti-proliferative evaluation of novel quinoxaline derivatives as potential DNA intercalators and topoisomerase II inhibitors
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New series of [1,2,4]triazolo [4,3-a]quinoxaline and bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives have been designed, synthesized and biologically evaluated for their cytotoxic activities against three tumor cell lines (HePG-2, Hep-2 and Caco-2). Compounds 16e, 21, 25a and 25b exhibited the highest activities against the examined cell lines with IC50 values ranging from 0.29 to 0.90 μM comparable to that of doxorubicin (IC50 ranging from 0.51 to 0.73 μM). The most active members were further evaluated for their topoisomerase II (Topo II) inhibitory activities and DNA intercalating affinities as potential mechanisms for their anti-proliferative activities. Interestingly, the results of Topo II inhibition and DNA binding assays were consistent with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited good Topo II inhibitory activities and DNA binding affinities, comparable to that of doxorubicin. Moreover, the most active compound 25a caused cell cycle arrest at G2/M phase and induced apoptosis in Caco-2 cells. In addition, Furthermore, molecular docking studies were performed for the novel compounds against DNA-Topo II complex to investigate their binding patterns. Based on these studies, it was concluded that DNA binding and/or Topo II inhibition may contribute to the observed cytotoxicity of the synthesized compounds.
- Ibrahim,Taghour,Metwaly,Belal,Mehany,Elhendawy,Radwan,Yassin,El-Deeb,Hafez,ElSohly,Eissa
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p. 117 - 134
(2018/06/08)
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- DNA topoisomerase II inhibition has the activity of modulating kui analogue and its preparation method and application
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The invention discloses a quinoxalinone analog with DNA (deoxyribonucleic acid) topoismerase II inhibiting activity, an optical isomer, diastereoisomer or racemic mixture, or pharmaceutically acceptable salt, solvate, prodrug, intermediate or metabolite thereof. The structural general formula is disclosed as Formula (I), wherein R1, R2, R3, R4, R5 and Ar are defined in the specification. The invention also discloses a preparation method of the compounds and application of the compounds as drugs and in treating tumors. The compounds have the advantages of definite curative effect and small toxic and side effects, enriches the varieties of inhibitors of drugs for treating diseases caused by topoismerase II expression abnormity in the prior art, and is hopeful to become clinical drugs with higher therapeutic index.
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Paragraph 0105; 0106; 0107
(2018/08/03)
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- Oxalic/malonic acids as carbon building blocks for benzazole, quinazoline and quinazolinone synthesis
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An oxidant, base and metal free methodology has been developed for the synthesis of various 2-substituted and non-substituted benzazoles, quinazolines and quinazolinones using oxalic/malonic acids as an in situ carbon source. This methodology is applicable for a wide range of substituted o-phenylenediamine, o-aminothiophenol, o-aminophenol and o-aminobenzamide containing various functional groups and provides good to excellent yields of the corresponding product. Furthermore an easy workup procedure, high yield and easy isolation of products are key features of this methodology. The developed protocol is also applicable for the gram scale synthesis of benzimidazoles.
- Sharma, Saurabh,Bhattacherjee, Dhananjay,Das, Pralay
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supporting information
p. 1337 - 1342
(2018/03/06)
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- Synthesis and evaluation of the anticonvulsant activities of new 5-substitued-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one derivatives
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Background: Eplilepsy is defined as one of the most common neurological diseases, which affects approximately 50 million people all over the word. Despite the development of several new antiseizure drugs, the treatment of epilepsy remains still inadequate, because generally, anticonvulsant drugs can cause serious side effects such as neurotoxicity, depression, and impaired memory function. It is therefore imperative to search for new, safer, and more effective drugs for epilepsy. Methods: All the synthesized compounds were evaluated their anticonvulsant activities by the Maximal electroshock seizure and chemical-induced seizures models. The neurotoxicity of the compounds was measured in mice by the rotarod test. Results: Twenty 5-substitued-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one derivatives were synthesized and evaluated for anticonvulsant activities. Compound 5d was the most potent with an ED50 value of 27.39 mg/kg and a PI of 24.99. It also protected against seizures induced by pentylenetetrazole and bicuculline. In addition, compound 5d exhibited an ED50 value of 76.1 mg/kg and a PI > 39.44 following oral administration. Conclusion: All the synthesized compounds were confirmed by IR, 1H-NMR, 13C-NMR, and Mass spectra. Compound 5-hexyl-[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (5d) was safer than the commercially available drugs carbamazepine by administration of i.p in MES test. It also protected against seizures induced by chemical substances. Compound 5d should be a potential oral agent for treatment of epilepsy.
- Zhang, Guo-Rui,Ren, Yang,Yin, Xiu-Mei,Quan, Zhe-Shan
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p. 406 - 413
(2018/04/20)
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- Rationalization of benzazole-2-carboxylate versus benzazine-3-one/ benzazine-2,3-dione selectivity switch during cyclocondensation of 2-aminothiophenols/phenols/anilines with 1,2-biselectrophiles in aqueous medium
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The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as ethyl glyoxalate and diethyl oxalate in aqueous medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. On the other hand, the reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chemical calculations (density functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates versus benzazine-3-ones/ benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.
- Dhameliya, Tejas M.,Chourasiya, Sumit S.,Mishra, Eshan,Jadhavar, Pradeep S.,Bharatam, Prasad V.,Chakraborti, Asit K.
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p. 10077 - 10091
(2018/05/31)
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- Design, synthesis, biological evaluation and molecular docking study on peptidomimetic analogues of XK469
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XK469 is identified as a potent quinoxaline antineoplastic agent based on its significant clinical efficacy. It probably exerts its activity via DNA topoisomerase II (topo II) inhibition. To obtain more effective antineoplastic agents, a spectrum of peptidomimetic-type quinoxaline analogues of XK469 was herein designed, synthesized, and evaluated. Few compounds (e.g. 13a and 13b) exhibited obvious cytotoxicity indicated by in?vitro anti-proliferative assay. SAR investigation revealed that introducing of hydrophobic tert-butylamine or dodecylamine moiety at the 3-position of quinoxaline core is favorable for achieving a better anti-proliferative potency, while peptidomimetic derivatives only yielded moderate cytotoxicity. Compounds with improved anti-proliferative activities also demonstrated decent anti-metastatic potencies comparable with that of doxorubicin (Doxo) based on in?vivo mouse model study. The topo II-mediated kinetoplast DNA (kDNA) decatenation assay as well as molecular docking studies implicated that these compounds tend to be potent topo II inhibitors. Overall, compounds 13a and 13b, 13b in particular, standed out from various assessments and might be promising candidates for further chemical optimization.
- Xia, Qiao-Hong,Hu, Wei,Li, Chen,Wu, Ji-Feng,Yang, Liang,Han, Xue-Mei,Shen, Yue-Mao,Li, Zhi-Yu,Li, Xun
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supporting information
p. 311 - 325
(2016/09/07)
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- A kind of 2-hydrazone-thiazolo [4,5-b] quinoxaline compound and its preparation and use
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The invention relates to 2-hydrazone-thiazolo[4,5-b]quinoxaline compounds which are characterized in that the compounds have a general formula represented as the following, wherein R is as the following. The 2-hydrazone-thiazolo[4,5-b]quinoxaline compounds provided by the invention can be used as potential antibacterial and antitumor medicines. The invention also discloses a preparation method thereof.
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Paragraph 0015; 0016; 0025
(2017/01/09)
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